Lecture Course in Drug Discovery and Molecular Design
Professor Klaus Müller (F. Hoffmann-La Roche AG)
Latvian Institute of Organic Synthesis, Riga
Aizkraukles str.21, Small conference hall , 3rd floor
14.00 – 16.00 lecture
16.00 – 16.30 questions, discussion.
Monday, 4th November
Lecture 1 : Changing Environments and Paradigm Shifts for
Comments: It is important to give the audience an appreciation of the current multi-disciplinary environment within which modern drug discovery, and in particular, medicinal chemistry, is performed. Furthermore, it would be important to put the various technologies and methodologies into their historical context over the past three decades so that their rise and impact in Drug Discovery as well as further developments will be better understood. This also provides an excellent introduction to many aspects that will be discussed during the Course.
Tuesday, 5th November
Lecture 2 : Conformational Pitfalls in Molecular Design
Comments: Conformational aspects are of paramount importance in Molecular Modeling. Still today one can witness improper modeling, even by CAMM experts and in publications; automatic 3D-model generation programs often fail to produce proper molecular conformations. As much as possible, critical aspects of modeled and protein-docked molecular structures should be checked against experimental low-energy structures, e.g. by interrogating the Cambridge Structure Database (CSD). However, very often a modeled or docked structure looks so harmless and seemingly correct that no flags are risen to question certain conformational aspects. This Lecture discusses some of the most recurrent errors in structural modeling in order to provide a frame of reference for typical modeling applications.
Wednesday, 6th November
Lecture 3: Privileged Structures in Molecular Design
Comments: Some core molecular structures, in particular heterocyclic moieties, have over the years proved very promising in the design of potent ligands to diverse targets. In retrospect, such core structures are considered ‘privileged structures’ in drug discovery. This Lecture provides criteria to recognize a potentially ‘privileged core structure’ prospectively and illustrates the concepts by a number of prototypic cases.
Thursday, 7th November
Lecture 4 : 7-Membered Heterocycles:
A Treasury Box for Molecular Design
Comments: While 5- and 6-membered heterocycles have been abundantly in Molecular Design, 7-membered heterocycles are less frequently used and, if so, their incorporation into a molecular structure follows more topological arguments than 3D-structural criteria. This Lecture focuses on a set of simple rules that can be applied to guess the preferred conformation of a given 7-membered heterocyclic moiety and the characteristic spatial disposition for important substitution patterns; it also highlights aspects of ring annelations and conformational fixation. Some of the unique aspects of 7-membered rings, as compared to 6-membered counterparts, are also discussed.
Monday, 11th November
Lecture 5 : The Sulfone Unit in Drug Discovery
Comments: The sulfone (SO2) unit is an important and recurrent unit in Drug Discovery. Introduction of a sulfone unit results in a number of dramatic conformational and property changes of the target molecule. This Lecture summarizes and illustrates the key effects that are exerted on a structure by a SO2 unit.
12th November 14.00-16.00
Lecture 6 : Fluorine in Drug Discovery
Comments: The introduction of fluorine or fluorine-containing small groups into lead molecular structures has been a common modality in lead optimization; it leads to a multitude of effects on physicochemical and pharmacological properties. Systematic studies on such effects over the last 10-15 years have resulted in concepts that enable more rational approaches for the introduction of fluorine. This Lecture discusses and illustrates the concepts based on property and structural changes upon incorporation of fluorine.
13th November 14.00-16.00
Lecture 7 : Polar Lipocompatible Units in Drug Discovery
Comments: Polar groups of a molecule are typically assumed to remain exposed to the polar (water) environment upon binding of the molecule to a hydrophobic pocket of the target protein. While this is true in most of the cases, there are nevertheless a number of polar groups that are equally well accommodated within lipophilic protein pockets; these ‘polar lipocompatible’ groups play an important role in the design of protein-targeted molecules. Most important representatives of such ‘polar lipocompatible’ groups will be discussed in this Lecture.
14th November 14.00-16.00
Lecture 8 : Hydrogen Bonding: an Old Theme with New Variations
Comments: Hydrogen bonding is well recognized as an important non-covalent interaction for the binding of small molecules to protein targets. While the essential features of hydrogen bonding are well-understood and discussed in every chemical textbook, there are various misconceptions based on incomplete understanding of the nature of hydrogen bonding. This Lecture discusses important aspects of hydrogen bonding for protein-ligand complexes, in particular focusing and illustrating those cases which are important but less well recognized.
Lectures beyond: Expansions on Selected Topics
Comments: Most topics summarized above could be expanded into lectures over 4-6 hours. However, the Course is meant to provide a succinct tour through key aspects and a framework of reference for structure-based modeling, rather than comprehensive reviews on each topic. Furthermore, most of the topics are under continuous developments with more insights arising from additional experimental data.